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Randomized trials have demonstrated the clinical superiority of timely transfer for primary percutaneous coronary intervention (PCI) compared with onsite fibrinolytic therapy for reperfusion in the setting of ST-segment–elevation myocardial infarction (STEMI).1,2 On this point, there is relative clarity. What remains nebulous, however, is the degree to which these findings apply broadly across care systems that often have substantial transfer delays.

Providers continue to face the challenging question posed by transfer delays: How long is too long to justify transfer of STEMI patients for primary PCI? The American College of Cardiology/American Heart Association guidelines have, until recently, called for transfer for primary PCI when reperfusion can be accomplished within 90 minutes of initial presentation to the non-PCI center or with a PCI-related delay (time interval from when fibrinolytic therapy can be given until when PCI can be performed) of <60 minutes.3 The latest ACCF/AHA/SCAI guidelines for PCI extend the acceptable first door-to-device time to 120 minutes for patients presenting to non-PCI-capable hospitals, an adjustment in line with current European guidelines.4,4a The Figure depicts the temporal anatomy of a transfer, the key time-based elements of the reperfusion delivery process. The guidelines acknowledge that the selection of reperfusion method also hinges on additional variables, such as time since symptom onset, risk of death, and relative or absolute contraindications to fibrinolysis.3 Moreover, the guidelines emphasize that the selected method of reperfusion may be less important than the use of some type of reperfusion for all eligible patients in a timely fashion. Regional systems of care (as supported by Mission: Lifeline5) have been identified as essential elements of optimal care provision.

ST-segment–elevation myocardial infarction reperfusion pathways for non–percutaneous coronary intervention (PCI) centers. For the primary PCI pathway, both the latest American College of Cardiology/American Heart Association (ACC/AHA) guidelines and the European Society of Cardiology (ESC) guidelines call for times from first medical contact (often first door) to device within 120 minutes. The primary PCI pathway has 3 time elements: 1 door-in–door-out time, representing the time span from non-PCI center arrival to departure from the non-PCI center; 2 transfer time, representing the travel time span from non-PCI center departure to PCI center arrival; and 3 catheterization laboratory (Cath Lab) time, representing the time span from PCI center arrival to device deployment time in the catheterization laboratory. To avoid excessive transfer delays, the diagnosis and call for transport from a non-PCI center should occur within 15 minutes of a patient's arrival at the non-PCI center. For the fibrinolytic pathway, the goal is achievement of door-to-needle times within 30 minutes. For either pathway, an ECG should be obtained within 10 minutes of initial patient presentation. t Indicates time from first hospital arrival.

Despite the lack of clear standards, transfer decisions must be made for all of the estimated 40% of STEMI patients who present to non–PCI-capable hospitals in the United States. Five important lines of evidence form the basis for guiding these decisions:

Delay in reperfusion is associated with larger infarcts and higher mortality, with fibrinolytic therapy, and with primary PCI. Each hour of system delay to primary PCI is associated with an ≈10% increased risk of both death6 and heart failure, prompting readmission or outpatient visits.7 A unit of time delay in earlier hours after coronary occlusion is more harmful than in later hours.6

Primary PCI prevents more deaths than fibrinolytic therapy when delivered as it was in randomized trials in a timely fashion by experienced operators.8

Transfer for primary PCI is as good as or better than fibrinolytic therapy based on randomized trials,9 with overall door-to-balloon time in the range of 110 minutes in the largest single trial.1

Randomized trial results, when examined according to PCI-related delay, demonstrate primary PCI superiority up until about a 60-minute delay, at least with regard to fibrin-specific fibrinolytic agents.8,10,11 A meta-analysis suggested that longer hospital-level delays may still be associated with survival benefit with primary PCI,12 although there are limitations to these analyses.13

Observational studies have compared fibrinolytic-treated patients with primary PCI–treated patients across various levels of delay, with attempted adjustment for confounding factors. These studies suggest that primary PCI is associated with lower mortality when PCI-related delay is <114 minutes on average, but with large variability, depending on patient factors such as symptom duration, age, and infarct location.14

In the current issue of Circulation, Pinto and colleagues15 extend their prior analyses14 to evaluate the impact of transfer delays on the clinical advantages conferred by transfer for primary PCI over onsite fibrinolysis for reperfusion in STEMI patients. Assessed outcomes included in-hospital death, in-hospital recurrent MI, and in-hospital stroke. The authors hypothesized that the relative advantage of primary PCI would decline with increasing transfer-associated time delays. The observational study design used STEMI patient data from the National Registry of Myocardial Infarction over the 12-year period between 1994 and 2006. In an effort to address differences in baseline characteristics and risk profiles between the comparison groups, careful and comprehensive propensity score matching was used. For each of the 9506 matched pairs, PCI-associated time delay was calculated by subtracting door-to-needle time from first-door-to-balloon time.

Analysis of the matched pairs revealed statistically similar overall survival rates between the transfer for primary PCI and fibrinolysis groups (4.8% versus 6.2%). There were, however, overall lower rates of combined death/MI (5.9% versus 8.5%) and combined death/MI/stroke (6.3% versus 9.3%) in the primary PCI group. For the matched pairs in whom PCI-related delay was <60 minutes (n=2956), primary PCI was associated with statistically significant advantages over fibrinolytic therapy for several outcome categories: in-hospital death (2.7% versus 7.4%), death/MI (3.9% versus 9.3%), and death/MI/stroke (4.3% versus 10.6%). The 75% relative reduction in mortality, far greater than seen in randomized trials that typically included patients with this degree of delay, suggests incomplete adjustment of confounding factors. For delays of 61 to 90 minutes (n=3208), primary PCI remained associated with statistically significant advantages for the combined end points of death/MI and death/MI/stroke, but was no longer statistically superior to fibrinolysis for in-hospital death alone. Finally, for the matched pairs in whom PCI-related delay exceeded 90 minutes (n=12 848), primary PCI was statistically advantageous over fibrinolytic therapy for the occurrence of stroke, and in-hospital death remained nonsignificantly lower with primary PCI.

Equipoise calculations via conditional logistic regression indicated no mortality advantage for primary PCI over fibrinolysis when PCI-related delay exceeded 121 minutes, a threshold exceeded in 48% of studied patients. For the combined end point of death/MI/stroke, equipoise occurred at 158 minutes.

The authors conclude that there is a decline in mortality advantage for primary PCI over fibrinolysis as PCI-related delay increases and that, even with substantial PCI-related delays, there was no excess in mortality for the transferred primary PCI group compared with the fibrinolytic group.

Using a large data set, carefully analyzed with advanced statistical methods, Pinto and colleagues appear to have provided the most informative analysis possible with these data. However, there are major limitations inherent to any such observational analyses that prevent reliable inference of treatment effect.

The authors acknowledge the limitations of observational analyses and of addressing bias via propensity score matching. Although propensity scoring may help reduce certain types of bias, significant biases will almost certainly remain in the form of unobserved or unmeasured confounders. In this study, there are several potential examples of such confounders: longer overall care delays that might occur for sicker patients, differentially longer delays for fibrinolytic-treated patients, a tendency to favor primary PCI for healthier patients, and the exclusion of patients who had coronary angiography but no primary PCI, who make up a high-risk group related to complex factors. The impact of such confounders can be both potentially profound and impossible to definitively address. A recent example of careful analysis using propensity adjustment examined the impact of statins in heart failure.16 A 25% relative reduction in mortality was estimated in the carefully conducted observational study, followed by 2 large randomized clinical trials showing no effect of statins on mortality in patients with chronic heart failure.17,18

In fact, highly sophisticated analytic techniques such as propensity score matching may provide false reassurance to some readers that confounding is removed. Ironically, we may tend to believe this type of complex analysis of varying treatment effects according to differential administration times, which is a subgroup analysis of an observational treatment comparison. On the other hand, we tend to reject simple comparisons of 2 treatments from observational studies, which we customarily discount as hopelessly confounded. The adjustment techniques are only as reliable as their inescapable limitations permit them to be. Therefore, observational study findings should generally be considered hypothesis generating, and we should depend on randomization as the only definitive way to control for confounding caused by baseline differences.

We may never have a definitive clinical trial to define the time intervals that favor transfer for primary PCI. Our efforts should remain unrelenting in improving transfer systems to reduce first-door-to-device time for patients presenting to non–PCI-capable hospitals. An important practice evolution has occurred in the realm of field triage, whereby emergency medical services–diagnosed STEMI cases are transported directly to a PCI center, even if farther away than a non–PCI-capable hospital. Until we can collectively and conclusively identify the circumstances that define how long is too long, some uncertainty will persist, and the guidelines will remain the standard by which practitioners integrate the various lines of evidence outlined above. The benefits of timely fibrinolytic therapy are clear when delays (longer than the first-door-to-device-time of 90–120 minutes defined in the guidelines) persist. The ongoing Strategic Reperfusion Early After Myocardial Infarction (STREAM) trial evaluating immediate fibrinolytic therapy (including in the prehospital setting) versus primary PCI will add to the evidence.19

Registry studies play a key role in performance measurement, in carefully extending trial results to broader populations, and in placing trials in perspective. However, we should avoid the lure of observational analyses—even very high-quality ones—to estimate treatment effects.

Disclosures

None.

Footnotes

The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.

. 2007 Focused update of the ACC/AHA 2004 guidelines for the management of patients with ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines: developed in collaboration with the Canadian Cardiovascular Society endorsed by the American Academy of Family Physicians: 2007 Writing Group to Review New Evidence and Update the ACC/AHA 2004 Guidelines for the Management of Patients with ST-Elevation Myocardial Infarction, writing on behalf of the 2004 Writing Committee. Circulation. 2008;117:296–329.